Tissue inhibitors of metalloproteases (TIMPs) inhibit metalloproteases, a family of endopeptide hydrolases. Metalloproteases are secreted by connective tissue and hematopoietic cells, use Zn2+ or Ca2+ for catalysis, and may be inactivated by metal chelators as well as TIMP molecules. Matrix metalloproteases (MMPs) participate in a variety of biologically important processes, including the degradation of many structural components of tissues, particularly the extracellular matrix (ECM).
Degradation of extracellular matrix tissue is desirable in processes where destruction of existing tissues is necessary, e.g., in embryo implantation (Reponen et al., Dev. Dyn. 202, 388-96, 1995), embryogenesis, and tissue remodeling. Imbalance between synthesis and degradation of matrix proteins, however, can result in diseases such as liver fibrosis (Iredale et al., Hepatology 24, 176-84, 1996). This imbalance can occur, for example, if levels of TIMPs are increased. Disorders in which TIMP-1 levels of increased include, for example, liver fibrosis, alcoholic liver disease, cardiac fibrosis, acute coronary syndrome, lupus nephritis, glomerulosclerotic renal disease, idiopathic pulmonary fibrosis, benign prostate hypertrophy, lung cancer, and colon cancer. See, e.g., Inokubo et al., Am. Heart J 141, 211-17, 2001; Ylisirnio et al., Anticancer Res. 20, 1311-16, 2000; Holten-Andersen et al., Clin. Cancer Res. 6, 4292-99, 2000; Holten-Andersen et al., Br. J. Cancer 80, 495-503, 1999; Peterson et al., Cardiovascular Res. 46, 307-15, 2000; Arthur et al., Alcoholism: Clinical and Experimental Res. 23, 840-43, 1999; Iredale et al., Hepatol. 24, 176-84, 1996.
There is a need in the art for reagents and methods of inhibiting TIMP-1 activity, which can be used to provide therapeutic effects.